Genes to Therapies: One Year Later

Posted February 12, 2016

In just its first year of operation, Cure Alzheimer’s Fund’s ambitious new Genes to Therapies™ (G2T) research program has bloomed far beyond expectations.

“We’re firing on all cylinders now,” says Research Consortium Chair Dr. Rudy Tanzi. “It’s exactly where we need to be headed to stop this disease.”

In 2015, Cure Alzheimer’s Fund authorized nearly $6.8 million for 22 gene variant investigations, along with the initiation of 21 transgenic mouse models. That accounts for more than half of its total research funding this year—and is far more than all of its research funding in 2014.

G2T is the next phase of Cure Alzheimer’s Fund’s long-term plan for attacking Alzheimer’s disease from every possible angle. The key to defeating Alzheimer’s, Tanzi proposed 11 years ago, is first to identify, and then closely examine, the relevant genetic variants impacting disease risk. The identification phase was accomplished through two methods—Genome-Wide Association Studies (GWAS) and Whole Genome Sequencing (WGS)—which together located nearly 100 gene variants that impact Alzheimer’s risk.

By 2014, the Research Consortium and the Cure Alzheimer’s board recognized that we were ready for the next phase: G2T, where researchers now would investigate the precise function of each gene, the consequence of each variant and precisely how to intervene to arrest the disease process. Tanzi explains that G2T establishes a highly efficient research plan. “We’re not just studying genes at random anymore,” he says. “We know to a certainty that these particular genes impact Alzheimer’s. Now we can use our new mouse models to find the ones that are druggable. If we can find a switch that turns on a deleterious gene mutation, we want to turn that switch off.”

Prioritizing these variants and recruiting the appropriate research talent to examine each one requires vision and coordination. To guide this process, Cure Alzheimer’s Fund formed the G2T Steering Committee of leading Alzheimer’s researchers David Holtzman, M.D. (Washington University, St. Louis), Sangram Sisodia, Ph.D. (University of Chicago), Rudy Tanzi, Ph.D. (Massachusetts General Hospital/Harvard University), Robert Vassar, Ph.D. (Northwestern University), and Steven Wagner, Ph.D. (University of California, San Diego). That group then set the priorities for gene investigations and implemented the time-saving idea of developing appropriate mouse models even before recruiting the appropriate researchers. Early G2T researchers include G2T Steering Committee members, as well as Berislav Zlokovic, M.D., Ph.D. (University of Southern California), and Li-Huei Tsai, Ph.D. (MIT). 

Each gene to be studied may have several different mutations, each requiring its own strain of mice to study how that mutation affects Alzheimer’s pathology. Originally, the first year of G2T was expected to involve just three to five new animal models and cost a few hundred thousand dollars. But the Research Consortium’s strong support for the project quickly expanded it to 21 separate mouse models in 2015.

“This rapid expansion is a testament to both our researchers and our contributors,” says Cure Alzheimer’s Fund Chairman Jeffrey Morby. “The participating researchers have accelerated their work to a point where we can now take advantage of new techniques and breakthroughs. Meanwhile, our generous contributors have stepped up with dramatically larger donations, which has enabled us to fund more promising projects than ever before. It’s a remarkable confluence.”

The G2T Steering Committee recruited Wilma Wasco, Ph.D. (Massachusetts General Hospital), a geneticist and longtime colleague of Tanzi and other members of the Steering Committee, to manage the Genes to Therapies research core. Her expertise in Alzheimer’s genetics-driven research and her science management experience make her an ideal fit. “This is an immensely difficult job with a mind-numbing amount of important details and many different strong personalities,” explains Sisodia, a member of the Research Consortium and G2T Steering Committee. Tanzi concurs: “Wilma understands the science inside and out, and she also knows how to make the trains run on time. She’s perfect.”

This is the first time a genes-to-therapies program of this scale has been attempted, and it already has drawn the attention of the National Institutes of Health (NIH). In fact, the NIH has indicated interest in modeling a mouse program of its own on Cure Alzheimer’s G2T template. “That’s an incredible compliment,” says Cure Alzheimer’s CEO Tim Armour. “We’re humbled. It’s yet another way we continue to collaborate with NIH and take advantage of the scale they bring to the research effort.” 

Dr. Wasco also remarks how the G2T program dovetails very nicely with the recent “Alzheimer’s in a Dish” technology developed by Tanzi and Doo Yeon Kim, Ph.D. “They’re really complimentary,” says Wasco. “Alzheimer’s in a Dish is a great model and it will make things much faster for studying drugs. It’s a way to quickly find therapies. But eventually, any drug that you find has to be tested in animals for safety purposes and overall understanding of what’s going on.” 

No treatment will emerge quickly, Wasco cautions. “It takes a lot of patience to be in science,” she says. “As therapies become available, we’ll be able to test them. G2T projects funded in 2015 are already producing new insights into the function of variants we know impact Alzheimer’s risk, and that is a necessary step toward targeting their operation
with a treatment someday.”

“We have very high hopes for this project and are immensely proud of its ambitious scope,” says Morby. “We’re pressing forward with all the energy possible. Full steam ahead!”